Insulin resistance expression

The metabolic abnormalities of type 2 diabetes mellitus are the result of insulin resistance expressed primarily in liver, muscle, and adipose tissue (Figure 25.10). 

PPARy is a transcription factor which controls the expression of enzymes and proteins involved in fat and glucose metabolism. More importantly, stimulation of this receptor induces differentiation of preadipocytes to adipose cells. It is believed that the formation of additional, small fat cells lowers free fatty acids and hepatic triglycerides, thereby collecting insulin resistance. 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

Mutations in GK (Hx IV) causes maturity-onset diabetes of the young (MOD Y), a form of non-insulin-dependent diabetes mellitus (NIDDM) characterized by onset before 25 years of age and an autosomal dominant inheritance (PI 2). This suggests that the mutations in other forms of Hx may also contribute to the development of NIDDM. Among them, Hx II is a particularly attractive candidate, although this isozyme is not expressed in red blood cells. Hx II has been analyzed extensively in the muscle of prediabetic insulin-resistant individuals. But studies have shown that Hx II mutation alone is unlikely to have a significant role in the development of peripheral insulin resistance and NIDDM (L6). 

Kaaman M, Ryden M, Axelsson T, et al. (2006) ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance. Int J Obes (Land). 30, 447-452. 

Insulin-resistant rats muscle Increased expression Cao et al., 2007... 

Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha Direct role in obesity-linked insulin resistance. Science 1993 259 87-91. 

Two independent kindreds with insulin-resistant type 2 diabetes in association with novel PPARy mutations were recently described (64). In both cases, the mutations—Val—>Met290 and Pro—>Leu467—were shown to function as dominant-negative proteins when expressed in transfected cells. This compelling story provides further proof of the role of PPARy as a potential regulator of in vivo insulin action. 

Weinstein, S. P., Holand, A., O Boyle, E., and Haber, R. S. (1993). Effects of Thia-zolidinediones on Glucocorticoid-Induced Insulin Resistance and GLUT4 Glucose Transporter Expression in Rat Skeletal Muscle. Metabolism 42, 1365-1369. 

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